Physiologically based pharmacokinetic model for the inhibition of acetylcholinesterase by organophosphate esters.
Physiologically based pharmacokinetic model for the inhibition of acetylcholinesterase by organophosphate esters.
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DOI：
10.1289/ehp.94102s1151
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发表时间：
1994-12
影响因子：
10.4
通讯作者：
Conolly, R B
中科院分区：
文献类型：
--
作者：
Gearhart, J M;Jepson, G W;Clewell, H J;Andersen, M E;Conolly, R B
有机磷（OP）暴露在高剂量下可能是致命的，而低剂量可能会损害关键任务的性能。如果能够预测实际暴露情况下的此类影响，将大大改善OP风险评估。为此，二异丙基氟磷酸盐（DFP）的药代动力学和乙酰胆碱酯酶（AChE）抑制的生理基础模型的开发。在大鼠组织匀浆中测定DFP组织/血液分配系数、酯酶水解DFP的速率和DFP-酯酶双分子抑制速率常数。使用标准异速生长关系对大鼠和小鼠的其他模型参数进行缩放。这些DFP特异性参数值与模型一起用于模拟小鼠和大鼠的药代动力学数据。文献数据用于模型验证。DFP在小鼠血浆和脑中的浓度，以及AChE抑制和AChE再合成数据，成功地模拟了单次静脉注射。重复皮下注射DFP对大鼠血浆和大脑中AChE活性的影响也得到了很好的模拟，除了最后一次给药后35天大脑中基础AChE活性明显降低。基于心理学的药代动力学（PBPK）模型参数值，具体为DFP在人类中，例如，组织/血液分配系数，酶和非酶DFP水解速率，和双分子抑制速率常数为目标酶的啮齿动物数据缩放或从文献中获得。在肌肉注射33微克/千克DFP后和急性剂量DFP（10-54微克/千克）后24小时以及重复DFP暴露后，模型预测和人体暴露数据对红细胞AChE和血浆丁酰胆碱酯酶的抑制作用之间取得了良好的一致性。（250字处删节）
Organophosphate (OP) exposure can be lethal at high doses while lower doses may impair performance of critical tasks. The ability to predict such effects for realistic exposure scenarios would greatly improve OP risk assessment. To this end, a physiologically based model for diisopropylfluorophosphate (DFP) pharmacokinetics and acetylcholinesterase (AChE) inhibition was developed. DFP tissue/blood partition coefficients, rates of DFP hydrolysis by esterases, and DFP-esterase bimolecular inhibition rate constants were determined in rat tissue homogenates. Other model parameters were scaled for rats and mice using standard allometric relationships. These DFP-specific parameter values were used with the model to simulate pharmacokinetic data from mice and rats. Literature data were used for model validation. DFP concentrations in mouse plasma and brain, as well as AChE inhibition and AChE resynthesis data, were successfully simulated for a single iv injection. Effects of repeated, subcutaneous DFP dosing on AChE activity in rat plasma and brain were also well simulated except for an apparent decrease in basal AChE activity in the brain which persisted 35 days after the last dose. The psychologically based pharmacokinetic (PBPK) model parameter values specific for DFP in humans, for example, tissue/blood partition coefficients, enzymatic and nonenzymatic DFP hydrolysis rates, and bimolecular inhibition rate constants for target enzymes were scaled from rodent data or obtained from the literature. Good agreement was obtained between model predictions and human exposure data on the inhibition of red blood cell AChE and plasma butyrylcholinesterase after an intramuscular injection of 33 micrograms/kg DFP and at 24 hr after acute doses of DFP (10-54 micrograms/kg), as well as for repeated DFP exposures.(ABSTRACT TRUNCATED AT 250 WORDS)